1. Field of the Invention
The invention relates to processes for preparing amides of retinoic acid. In particular, the invention provides a procedure for producing N-(4-hydroxyphenyl)retinamide (fenretinide) on a production scale. In one version of the invention, fenretinide is produced via activation of retinoic acid (tretinoin) via its corresponding mixed anhydride or mixed carbonate followed by reaction of the activated intermediate with 4-aminophenol. Other amides of retinoic acid and isomers of retinoic acid, such as the 9-cis-form (alitretinoin) or 13-cis-form (isotretinoin), are also known to have useful properties and can be made by this invention.
2. Description of the Related Art
Fenretinide (CAS# 65646-68-6) is currently in Phase I clinical trials for the treatment of childhood brain cancer. Previous syntheses of fenretinide involved the activation of retinoic acid with PCl3 (see FIG. 1 and U.S. Pat. No. 4,190,594 to Gander et al.), with SOCl2 (see Hong S. Sin et al., “Synthesis and Preliminary Biological Studies of Novel Retinamide Derivatives”, Bull. Korean Chem. Soc., Vol. 23, No. 12, pages 1806-1810, 2002), and with N,N′-Dicyclohexyl-carbodiimide (DCC) (see Sangmam et al., “A Simple, General and Efficient Method for O and N-Retinoylation”, Synthetic Communications 28(16), pages 2945-2958, 1998).
Another process has been developed in which retinoic acid is first activated as the acid chloride using the Vilsmeier reagent (dimethylchloro-formamidinium chloride). The acid chloride is then added to bis-(N, O)-trimethylsilyl-p-aminophenol (See FIG. 2 and U.S. Pat. No. 5,399,757 to Maryanoff).
However, these methods can be unsuitable for scale-up and therefore, there is a need for simpler, scaleable, and less expensive processes for preparing amides of retinoic acid such as fenretinide.